This research is directed towards the continued development of methods for the estimation of neurochemical alterations in patients by assessment of amine metabolites in cerebrospinal fluid (CSF). The potentials and limitations of CSF metabolite studies are explored along with non-specific factors which affect them. Probenecid which inhibits the removal of the metabolites from CSF into the blood is administered as part of these studies. In drug-free depressed patients a non-normal, but apparently bimodal distribution is evident for the serotonin metabolite (5HIAA) after probenecid administration. The "low" 5HIAA subgroup can be differentiated on the basis of later age of onset, poor response to imipramine, and predominance of females. Evaluation of psychoactive drug effects on metabolites have focused on time-dependent effects. VMA, an important metabolite of norepinephrine in the periphery, has been found to be a minor metabolite in the CSF; in depressed patients its concentration is low compared to neurological controls, manics, or acute schizophrenics, paralleling previous findings with MHPG, the major metabolite of norepinephrine in human brain. Amine metabolites in the CSF of alcoholics have been studied in collaboration with the Navy Hospital; an increase in 5HIAA was found in association with acute alcohol withdrawal. Levels of probenecid in the CSF have been found to correlate with metabolite accumulation.